Compounds, compositions, and methods for the treatment of cancers

ABSTRACT

The present teachings relate to compounds and compositions for treatment of cancers. In some embodiments, the composition comprises a platinum (IV) complex having at least one polar moiety as a ligand.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 15/652,563 filed Jul. 18, 2017, which is a divisional application ofU.S. application Ser. No. 15/108,547 filed Jun. 27, 2016, which is a 35U.S.C. § 371 U.S. National Stage Entry of International Application No.PCT/US2014/071160 filed Dec. 18, 2014, which claims the benefit ofpriority of U.S. Application No. 61/922,272 filed Dec. 31, 2013, thecontents of each of which are each incorporated herein by reference intheir entirety.

FIELD OF THE INVENTION

The invention relates to platinum based compounds, compositions, andmethods of using thereof.

BACKGROUND

Platinum-based drugs are among the most active and widely usedanticancer agents and cisplatin represents one of the threeFDA-approved, platinum-based cancer chemotherapeutics. Althoughcisplatin is effective against a number of solid tumors, especiallytesticular and ovarian cancer, its clinical use has been limited becauseof its toxic effects as well as the intrinsic and acquired resistance ofsome tumors to this drug.

To overcome these limitations, platinum analogs with lower toxicity andgreater activity in cisplatin-resistant tumors have been developed andtested, resulting in the approval of carboplatin and oxaliplatin in theUnited States. For example, carboplatin has the advantage of being lessnephrotoxic, but its cross-resistance with cisplatin has limited itsapplication in otherwise cisplatin-treatable diseases.

Oxaliplatin, however, exhibits a different anticancer spectrum from thatof cisplatin. It has been approved as the first or second line therapyin combination with 5-fluorouracil/leucovorin for advanced colorectalcancer, for which cisplatin and carboplatin are essentially inactive.These platinum drugs have platinum in the 2+ oxidative state (Pt(II))and are not orally active.

Platinum complexes in the 4+ oxidative state (Pt(IV) complexes) provideseveral advantages. The two additional coordination sites (the axialsites) can be modified to change the pharmacokinetic properties of thecomplexes. For example, the two axial sites, as well as the fourequatorial sites, can include ligands that have polar moieties. Notwishing to be bound by any theory, the polarity increase of the Pt(IV)complexes of the present teachings may increase the Pt concentration intumor cells. In certain instances, Pt(IV) complexes of the presentteachings can be orally active and/or have a reduced long-term toxicity.

SUMMARY

The present teachings relate to compositions, for example, for reducing,disrupting, or inhibiting the growth of a cancer cell or inducing thedeath of a cancer cell.

The composition can include a platinum (IV) compound. In variousembodiments, the platinum (IV) compound includes a polar moiety. Forexample, the polar moiety can be hydrophilic. In some embodiments, thepresent teachings provide a compound of Formula I:

-   -   or a pharmaceutically acceptable salt thereof,    -   wherein:    -   two of R¹, R², R³, and R⁴ each independently is a halide or a        carboxylate; the remaining two of R¹, R², R³, and R⁴ each        independently is an amine; and        -   X is absent, C(R⁵)₂, or NR⁵,        -   Y is absent, C(R⁶)₂, or NR⁶,    -   R⁵ and R⁶ independently at each occurrence is selected from        hydrogen, alkyl, alkenyl, alkynyl, ether, amine, and        carboxylate, wherein each of the alkyl, the alkenyl, the        alkynyl, the ether, and the amine groups optionally is        substituted with one or more groups, each independently selected        from halogen, hydroxyl, ether, alkoxy, and amine, wherein each        of the ether, the alkoxy, or the amine is optionally substituted        with one or more suitable substituents; and at least one of R¹,        R², R³, R⁴, R⁵, and R⁶ comprises a polar moiety.

The present teachings also provide compositions including a compound asdescribed herein and methods of using a compound or a composition asdescribed herein. In various embodiments, the methods of the presentteachings are useful for the prevention or treatment of diseases thatbenefit from increased cell death or decreased cell proliferation. Forexample, the method of the present teachings can be used to increasecancer cell death or decrease cancer cell proliferation. The increasedcancer cell death or decreased cancer proliferation can occur, forexample, outside the body (in vitro) or inside the body (in vivo).

Certain embodiments of the present teachings also provide for use of acompound as described herein as a medicament for treating or preventinga disease and/or in the manufacture of such a medicament, e.g., for usein the treatment of a disease. Some embodiments provide the use of acompound as described herein for use as a medicament. In certainembodiments, the teachings provide a compound or composition asdescribed herein for the treatment of disease, e.g. for the treatment ofa cancer.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows exemplary growth curves of Calu-6 tumor in nude micexenograft when the mice were dosed with control vehicle or an exemplarycompound of the present teachings.

FIG. 2 shows exemplary platinum levels in tumor when platinum (IV) wasdosed in the form of three exemplary compounds of the present teachingsand two comparison compounds to tumor-bearing nude mice via intravenousadministration.

DETAILED DESCRIPTION

For convenience, before further description of the present teachings,certain terms employed in the specification, examples, and appendedclaims are collected here. These definitions should be read in light ofthe remainder of the disclosure and as understood by a person ofordinary skill in the art. Unless defined otherwise, all technical andscientific terms used herein have the same meaning as commonlyunderstood by a person of ordinary skill in the art.

The articles “a” and “an,” as used herein, should be understood to mean“at least one,” unless clearly indicated to the contrary.

The phrase “and/or,” as used herein, should be understood to mean“either or both” of the elements so conjoined, i.e., elements that areconjunctively present in some cases and disjunctively present in othercases. Other elements may optionally be present other than the elementsspecifically identified by the “and/or” clause, whether related orunrelated to those elements specifically identified unless clearlyindicated to the contrary. Thus, as a non-limiting example, a referenceto “A and/or B,” when used in conjunction with open-ended language suchas “comprising” can refer, in one embodiment, to A without B (optionallyincluding elements other than B); in another embodiment, to B without A(optionally including elements other than A); in yet another embodiment,to both A and B (optionally including other elements).

As used herein, “or” should be understood to have the same meaning as“and/or” as defined above. For example, when separating items in a list,“or” or “and/or” shall be interpreted as being inclusive, i.e., theinclusion of at least one, but also including more than one, of a numberor list of elements, and, optionally, additional unlisted items. Onlyterms clearly indicated to the contrary, such as “only one of” or“exactly one of,” or, when used in the claims, “consisting of,” willrefer to the inclusion of exactly one element of a number or list ofelements.

In general, the term “or” as used herein shall only be interpreted asindicating exclusive alternatives (i.e. “one or the other but not both”)when preceded by terms of exclusivity, such as “either,” “one of,” “onlyone of,” or “exactly one of.” “Consisting essentially of,” when used inthe claims, shall have its ordinary meaning as used in the field ofpatent law.

As used herein, the phrase “at least one” in reference to a list of oneor more elements should be understood to mean at least one elementselected from any one or more of the elements in the list of elements,but not necessarily including at least one of each and every elementspecifically listed within the list of elements and not excluding anycombinations of elements in the list of elements. This definition alsoallows that elements may optionally be present other than the elementsspecifically identified within the list of elements to which the phrase“at least one” refers, whether related or unrelated to those elementsspecifically identified.

Thus, as a non-limiting example, “at least one of A and B” (or,equivalently, “at least one of A or B,” or, equivalently “at least oneof A and/or B”) can refer, in one embodiment, to at least one,optionally including more than one, A, with no B present (and optionallyincluding elements other than B); in another embodiment, to at leastone, optionally including more than one, B, with no A present (andoptionally including elements other than A); in yet another embodiment,to at least one, optionally including more than one, A, and at leastone, optionally including more than one, B (and optionally includingother elements); etc.

As used herein, all transitional phrases such as “comprising,”“including,” “carrying,” “having,” “containing,” “involving,” “holding,”and the like are to be understood to be open-ended, i.e., to meanincluding but not limited to.

Only the transitional phrases “consisting of” and “consistingessentially of” shall be closed or semi-closed transitional phrases,respectively, as set forth in the United States Patent Office Manual ofPatent Examining Procedures.

As used herein, a “subject” or a “patient” refers to any mammal (e.g., ahuman), such as a mammal that may be susceptible to a disease ordisorder, for example, tumorigenesis or cancer. Examples include ahuman, a non-human primate, a cow, a horse, a pig, a sheep, a goat, adog, a cat, or a rodent such as a mouse, a rat, a hamster, or a guineapig. In various embodiments, a subject refers to one that has been orwill be the object of treatment, observation, or experiment. Forexample, a subject can be a subject diagnosed with cancer or otherwiseknown to have cancer or one selected for treatment, observation, orexperiment on the basis of a known cancer in the subject.

As used herein, “treatment” or “treating” refers to an amelioration of adisease or disorder, or at least one discernible symptom thereof. Inanother embodiment, “treatment” or “treating” refers to an ameliorationof at least one measurable physical parameter, not necessarilydiscernible by the patient. In yet another embodiment, “treatment” or“treating” refers to reducing the progression of a disease or disorder,either physically, e.g., stabilization of a discernible symptom,physiologically, e.g., stabilization of a physical parameter, or both.In yet another embodiment, “treatment” or “treating” refers to delayingthe onset of a disease or disorder.

As used herein, “prevention” or “preventing” refers to a reduction ofthe risk of acquiring a given disease or disorder.

The phrase “therapeutically effective amount” as used herein means thatamount of a compound, material, or composition comprising a compound ofthe present teachings which is effective for producing some desiredtherapeutic effect. Accordingly, a therapeutically effective amounttreats or prevents a disease or a disorder. In various embodiments, thedisease or disorder is a cancer.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom (C).

By “optional” or “optionally,” it is meant that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where the event or circumstance occursand instances in which it does not. For example, “optionally substitutedaryl” encompasses both “aryl” and “substituted aryl” as defined herein.It will be understood by those ordinarily skilled in the art, withrespect to any group containing one or more substituents, that suchgroups are not intended to introduce any substitution or substitutionpatterns that are sterically impractical, synthetically non-feasible,and/or inherently unstable.

The term “alkyl” as used herein refers to a saturated straight orbranched hydrocarbon, such as a straight or branched group of 1-22, 1-8,1-6, or 1-4 carbon atoms, referred to herein as (C₁-C₂₂)alkyl,(C₁-C₈)alkyl, (C₁-C₆)alkyl, and (C₁-C₄)alkyl, respectively. Exemplaryalkyl groups include, but are not limited to, methyl, ethyl, propyl,isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, andoctyl.

The term “alkenyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon double bond(shown, for example, as “=”), such as a straight or branched group of2-22, 2-8, 2-6, or 2-4 carbon atoms, referred to herein as(C₂-C₂₂)alkenyl, (C₂-C₈)alkenyl, (C₂-C₆)alkenyl, and (C₂-C₄)alkenyl,respectively. Exemplary alkenyl groups include, but are not limited to,vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl,hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, and4-(2-methyl-3-butene)-pentenyl.

The term “alkynyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon triple bond(shown, for example, as “≡”), such as a straight or branched group of2-22, 2-8, 2-6, 2-4 carbon atoms, referred to herein as (C₂-C₂₂)alkynyl,(C₂-C₈)alkynyl, (C₂-C₆)alkynyl, and (C₂-C₄)alkynyl, respectively.Exemplary alkynyl groups include, but are not limited to, ethynyl,propynyl, butynyl, pentynyl, hexynyl, methylpropynyl,4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl.

The term “cycloalkyl” as used herein refers to a saturated orunsaturated monocyclic, bicyclic, other multicyclic, or bridged cyclichydrocarbon group. A cyclocalkyl group can have 3-22, 3-12, or 3-8 ringcarbons, referred to herein as (C₃-C₂₂)cycloalkyl, (C₃-C₁₂)cycloalkyl,or (C₃-C₈)cycloalkyl, respectively. A cycloalkyl group can also have oneor more carbon-carbon double bond or carbon-carbon triple bond.

Exemplary monocyclic cycloalkyl groups include, but are not limited to,cyclopentanes (cyclopentyls), cyclopentenes (cyclopentenyls),cyclohexanes (cyclohexyls), cyclohexenes (cyclopexenyls), cycloheptanes(cycloheptyls), cycloheptenes (cycloheptenyls), cyclooctanes(cyclooctyls), cyclooctenes (cyclooctenyls), cyclononanes (cyclononyls),cyclononenes (cyclononenyls), cyclodecanes (cyclodecyls), cyclodecenes(cyclodecenyls), cycloundecanes (cycloundecyls), cycloundecenes(cycloundecenyls), cyclododecanes (cyclododecyls), and cyclododecenes(cyclododecenyls). Other exemplary cycloalkyl groups, includingbicyclic, multicyclic, and bridged cyclic groups, include, but are notlimited to, bicyclobutanes (bicyclobutyls), bicyclopentanes(bicyclopentyls), bicyclohexanes (bicyclohexyls), bicycleheptanes(bicycloheptyls, including bicyclo[2,2,1]heptanes(bicycle[2,2,1]heptyls) and bicycle[3,2,0]heptanes(bicycle[3,2,0]heptyls)), bicyclooctanes (bicyclooctyls, includingoctahydropentalene (octahydropentalenyl), bicycle[3,2,1]octane(bicycle[3,2,1]octyl), and bicylo[2,2,2]octane (bicycle[2,2,2]octyl)),and adamantanes (adamantyls). Cycloalkyl groups can be fused to othercycloalkyl saturated or unsaturated, aryl, or heterocyclyl groups.

The term “aryl” as used herein refers to a mono-, bi-, or othermulti-carbocyclic aromatic ring system. The aryl can have 6-22, 6-18,6-14, or 6-10 carbons, referred to herein as (C₆-C₂₂)aryl, (C₆-C₁₈)aryl,(C₆-C₁₄)aryl, or (C₆-C₁₀)aryl, respectively. The aryl group canoptionally be fused to one or more rings selected from aryls,cycloalkyls, and heterocyclyls. The term “bicyclic aryl” as used hereinrefers to an aryl group fused to another aromatic or non-aromaticcarbocylic or heterocyclic ring. Exemplary aryl groups include, but arenot limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl,azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties suchas 5,6,7,8-tetrahydronaphthyl. Exemplary aryl groups also include, butare not limited to a monocyclic aromatic ring system, wherein the ringcomprises 6 carbon atoms, referred to herein as “(C₆)aryl” or phenyl.The phenyl group can also be fused to a cyclohexane or cyclopentane ringto form another aryl.

The term “arylalkyl” as used herein refers to an alkyl group having atleast one aryl substituent (e.g., -aryl-alkyl-). Exemplary arylalkylgroups include, but are not limited to, arylalkyls having a monocyclicaromatic ring system, wherein the ring comprises 6 carbon atoms,referred to herein as “(C₆)arylalkyl.” The term “benzyl” as used hereinrefers to the group —CH₂-phenyl.

The term “heteroalkyl” refers to an alkyl group as described herein inwhich one or more carbon atoms is replaced by a heteroatom. Suitableheteroatoms include oxygen, sulfur, nitrogen, phosphorus, and the like.Examples of heteroalkyl groups include, but are not limited to, alkoxy,amino, thioester, and the like.

The terms “heteroalkenyl” and “heteroalkynyl” refer to unsaturatedaliphatic groups analogous in length and possible substitution to theheteroalkyls described above, but that contain at least one double ortriple bond, respectively.

The term “heterocycle” refers to cyclic groups containing at least oneheteroatom as a ring atom, in some cases, 1 to 3 heteroatoms as ringatoms, with the remainder of the ring atoms being carbon atoms. Suitableheteroatoms include oxygen, sulfur, nitrogen, phosphorus, and the like.In some cases, the heterocycle may be 3- to 10-membered ring structuresor 3- to 7-membered rings, whose ring structures include one to fourheteroatoms. The term “heterocycle” may include heteroaryl groups,saturated heterocycles (e.g., cycloheteroalkyl) groups, or combinationsthereof. The heterocycle may be a saturated molecule, or may compriseone or more double bonds. In some case, the heterocycle is a nitrogenheterocycle, wherein at least one ring comprises at least one nitrogenring atom. The heterocycles may be fused to other rings to form apolycylic heterocycle. Thus, heterocycles also include bicyclic,tricyclic, and tetracyclic groups in which any of the above heterocyclicrings is fused to one or two rings independently selected from aryls,cycloalkyls, and heterocycles. The heterocycle may also be fused to aspirocyclic group.

Heterocycles include, for example, thiophene, benzothiophene,thianthrene, furan, tetrahydrofuran, pyran, isobenzofuran, chromene,xanthene, phenoxathiin, pyrrole, dihydropyrrole, pyrrolidine, imidazole,pyrazole, pyrazine, isothiazole, isoxazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine,quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine,quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,triazole, tetrazole, oxazole, isoxazole, thiazole, isothiazole,phenanthridine, acridine, pyrimidine, phenanthroline, phenazine,phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane,thiolane, oxazole, oxazine, piperidine, homopiperidine(hexamethyleneimine), piperazine (e.g., N-methyl piperazine),morpholine, lactones, lactams such as azetidinones and pyrrolidinones,sultams, sultones, other saturated and/or unsaturated derivativesthereof, and the like.

In some cases, the heterocycle may be bonded to a compound via aheteroatom ring atom (e.g., nitrogen). In some cases, the heterocyclemay be bonded to a compound via a carbon ring atom. In some cases, theheterocycle is pyridine, imidazole, pyrazine, pyrimidine, pyridazine,acridine, acridin-9-amine, bipyridine, naphthyridine, quinoline,isoquinoline, benzoquinoline, benzoisoquinoline,phenanthridine-1,9-diamine, or the like.

The term “heteroaromatic” or “heteroaryl” as used herein refers to amono-, bi-, or multi-cyclic aromatic ring system containing one or moreheteroatoms, for example 1-3 heteroatoms, such as nitrogen, oxygen, andsulfur. Heteroaryls can also be fused to non-aromatic rings. In variousembodiments, the term “heteroaromatic” or “heteroaryl,” as used hereinexcept where noted, represents a stable 5- to 7-membered monocyclic,stable 9- to 10-membered fused bicyclic, or stable 12- to 14-memberedfused tricyclic heterocyclic ring system which contains an aromatic ringthat contains at least one heteroatom selected from the group consistingof N, O, and S. In some embodiments, at least one nitrogen is in thearomatic ring.

Heteroaromatics or heteroaryls can include, but are not limited to, amonocyclic aromatic ring, wherein the ring comprises 2-5 carbon atomsand 1-3 heteroatoms, referred to herein as “(C₂-C₅)heteroaryl.”Illustrative examples of monocyclic heteroaromatic (or heteroaryl)include, but are not limited to, pyridine (pyridinyl), pyridazine(pyridazinyl), pyrimidine (pyrimidyl), pyrazine (pyrazyl), triazine(triazinyl), pyrrole (pyrrolyl), pyrazole (pyrazolyl), imidazole(imidazolyl), (1,2,3)- and (1,2,4)-triazole ((1,2,3)- and(1,2,4)-triazolyl), pyrazine (pyrazinyl), pyrimidine (pyrimidinyl),tetrazole (tetrazolyl), furan (furyl), thiophene (thienyl), isoxazole(isoxazolyl), thiazole (thiazolyl), isoxazole (isoxazolyl), and oxazole(oxazolyl).

The term “bicyclic heteroaromatic” or “bicyclic heteroaryl” as usedherein refers to a heteroaryl group fused to another aromatic ornon-aromatic carbocylic or heterocyclic ring. Exemplary bicyclicheteroaromatics or heteroaryls include, but are not limited to 5,6- or6,6-fused systems, wherein one or both rings contain heteroatoms. Theterm “bicyclic heteroaromatic” or “bicyclic heteroaryl” also encompassesreduced or partly reduced forms of fused aromatic system wherein one orboth rings contain ring heteroatoms. The ring system may contain up tothree heteroatoms, independently selected from oxygen, nitrogen, andsulfur.

Exemplary bicyclic heteroaromatics (or heteroaryls) include, but are notlimited to, quinazoline (quinazolinyl), benzoxazole (benzoxazolyl),benzothiophene (benzothiophenyl), benzoxazole (benzoxazolyl),benzisoxazole (benzisoxazolyl), benzimidazole (benzimidazolyl),benzothiazole (benzothiazolyl), benzofurane (benzofuranyl),benzisothiazole (benzisothiazolyl), indole (indolyl), indazole(indazolyl), indolizine (indolizinyl), quinoline (quinolinyl),isoquinoline (isoquinolinyl), naphthyridine (naphthyridyl), phthalazine(phthalazinyl), phthalazine (phthalazinyl), pteridine (pteridinyl),purine (purinyl), benzotriazole (benzotriazolyl), and benzofurane(benzofuranyl). In some embodiments, the bicyclic heteroaromatic (orbicyclic heteroaryl) is selected from quinazoline (quinazolinyl),benzimidazole (benzimidazolyl), benzothiazole (benzothiazolyl), indole(indolyl), quinoline (quinolinyl), isoquinoline (isoquinolinyl), andphthalazine (phthalazinyl). In certain embodiments, the bicyclicheteroaromatic (or bicyclic heteroaryl) is quinoline (quinolinyl) orisoquinoline (isoquinolinyl).

The term “tricyclic heteroaromatic” or “tricyclic heteroaryl” as usedherein refers to a bicyclic heteroaryl group fused to another aromaticor non-aromatic carbocylic or heterocyclic ring. The term “tricyclicheteroaromatic” or “tricyclic heteroaryl” also encompasses reduced orpartly reduced forms of fused aromatic system wherein one or both ringscontain ring heteroatoms. Each of the ring in the tricyclicheteroaromatic (tricyclic heteroaryl) may contain up to threeheteroatoms, independently selected from oxygen, nitrogen, and sulfur.

Exemplary tricyclic heteroaromatics (or heteroaryls) include, but arenot limited to, acridine (acridinyl), 9H-pyrido[3,4-b]indole(9H-pyrido[3,4-b]indolyl), phenanthridine (phenanthridinyl),pyrido[1,2-a]benzimidazole (pyrido[1,2-a]benzimidazolyl), andpyrido[1,2-b]indazole (pyrido[1,2-b]indazolyl).

The term “alkoxy” as used herein refers to an alkyl group attached to anoxygen (—O-alkyl-). “Alkoxy” groups also include an alkenyl groupattached to an oxygen (“alkenyloxy”) or an alkynyl group attached to anoxygen (“alkynyloxy”) groups. Exemplary alkoxy groups include, but arenot limited to, groups with an alkyl, alkenyl or alkynyl group of 1-22,1-8, or 1-6 carbon atoms, referred to herein as (C₁-C₂₂)alkoxy,(C₁-C₈)alkoxy, or (C₁-C₆)alkoxy, respectively. Exemplary alkoxy groupsinclude, but are not limited to methoxy and ethoxy.

The term “cycloalkoxy” as used herein refers to a cycloalkyl groupattached to an oxygen.

The term “aryloxy” or “aroxy” as used herein refers to an aryl groupattached to an oxygen atom. Exemplary aryloxy groups include, but arenot limited to, aryloxys having a monocyclic aromatic ring system,wherein the ring comprises 6 carbon atoms, referred to herein as“(C₆)aryloxy.” The term “arylalkoxy” as used herein refers to anarylalkyl group attached to an oxygen atom. An exemplary aryalkyl groupis benzyloxy group.

The term “amine” or “amino” as used herein refers to both unsubstitutedand substituted amines, e.g., NR_(a)R_(b)R_(b′), where R_(a), R_(b), andR_(b′) are independently selected from alkyl, alkenyl, alkynyl, aryl,arylalkyl, carbamate, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl,and hydrogen, and at least one of the R_(a), R_(b), and R_(b′) is nothydrogen. The amine or amino can be attached to the parent moleculargroup through the nitrogen. The amine or amino also may be cyclic, forexample any two of R_(a), R_(b), and R_(b′) may be joined togetherand/or with the N to form a 3- to 12-membered ring (e.g., morpholino orpiperidinyl). The term amino also includes the corresponding quaternaryammonium salt of any amino group. Exemplary amines include alkylamine,wherein at least one of R_(a) R_(b), or R_(b′) is an alkyl group, orcycloalkylamine, wherein at least one of R_(a) R_(b), or R_(b′) is acycloalkyl group.

The term “ammonia” as used herein refers to NH₃.

The term “aldehyde” or “formyl” as used herein refers to —CHO.

The term “acyl” term as used herein refers to a carbonyl radicalattached to an alkyl, alkenyl, alkynyl, cycloalkyl, heterocycyl, aryl,or heteroaryl. Exemplary acyl groups include, but are not limited to,acetyl, formyl, propionyl, benzoyl, and the like.

The term “amide” as used herein refers to the form —NR_(c)C(O)(R_(d))—or —C(O)NR_(c)R_(e), wherein R_(c), R_(d), and R_(e) are eachindependently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl,cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. The amidecan be attached to another group through the carbon, the nitrogen,R_(c), R_(d), or R_(e). The amide also may be cyclic, for example R_(c)and R_(e), may be joined to form a 3- to 12-membered ring, such as a 3-to 10-membered ring or a 5- or 6-membered ring. The term “amide”encompasses groups such as sulfonamide, urea, ureido, carbamate,carbamic acid, and cyclic versions thereof. The term “amide” alsoencompasses an amide group attached to a carboxy group, e.g.,-amide-COOH or salts such as -amide-COONa.

The term “arylthio” as used herein refers to an aryl group attached toan sulfur atom. Exemplary arylthio groups include, but are not limitedto, arylthios having a monocyclic aromatic ring system, wherein the ringcomprises 6 carbon atoms, referred to herein as “(C₆)arylthio.”

The term “arylsulfonyl” as used herein refers to an aryl group attachedto a sulfonyl group, e.g., —S(O)₂-aryl-. Exemplary arylsulfonyl groupsinclude, but are not limited to, arylsulfonyls having a monocyclicaromatic ring system, wherein the ring comprises 6 carbon atoms,referred to herein as “(C₆)arylsulfonyl.”

The term “carbamate” as used herein refers to the formR_(f)OC(O)N(R_(g))—, —R_(f)OC(O)N(R_(g))R_(h)—, or —OC(O)NR_(g)R_(h),wherein R_(f), R_(g), and R_(h) are each independently selected fromalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl,heteroaryl, heterocyclyl, and hydrogen. Exemplary carbamates include,but are not limited to, arylcarbamates or heteroaryl carbamates (e.g.,wherein at least one of R_(f), R_(g) and R_(h) are independentlyselected from aryl or heteroaryl, such as pyridinyl, pyridazinyl,pyrimidinyl, and pyrazinyl).

The term “carbonyl” as used herein refers to —C(O)—.

The term “carboxy” or “carboxylate” as used herein refers to R_(j)—COOHor its corresponding carboxylate salts (e.g., R_(j)—COONa), where R_(j)can independently be selected from alkoxy, aryloxy, alkyl, alkenyl,alkynyl, amide, amino, aryl, arylalkyl, cycloalkyl, ether, haloalkyl,heteroaryl, and heterocyclyl. Exemplary carboxys include, but are notlimited to, alkyl carboxy wherein R_(j) is alkyl, such as —O—C(O)-alkyl.Exemplary carboxy also include aryl or heteoraryl carboxy, e.g. whereinR_(j) is an aryl, such as phenyl and tolyl, or heteroaryl group such aspyridine, pyridazine, pyrmidine and pyrazine. The term carboxy alsoincludes “carboxycarbonyl,” e.g. a carboxy group attached to a carbonylgroup, e.g., —C(O)—COOH or salts, such as —C(O)—COONa.

The term “dicarboxylic acid” as used herein refers to a group containingat least two carboxylic acid groups such as saturated and unsaturatedhydrocarbon dicarboxylic acids and salts thereof. Exemplary dicarboxylicacids include alkyl dicarboxylic acids. Dicarboxylic acids include, butare not limited to succinic acid, glutaric acid, adipic acid, subericacid, sebacic acid, azelaic acid, maleic acid, phthalic acid, asparticacid, glutamic acid, malonic acid, fumaric acid, (+)/(−)-malic acid,(+)/(−) tartaric acid, isophthalic acid, and terephthalic acid.Dicarboxylic acids further include carboxylic acid derivatives thereof,such as anhydrides, imides, hydrazides (for example, succinic anhydrideand succinimide).

The term “cyano” as used herein refers to —CN.

The term “ester” refers to the structure —C(O)O—, —C(O)O—R_(i)—,—R_(j)C(O)O—R_(i)—, or —R_(j)C(O)O—, where 0 is not bound to hydrogen,and R_(i) and R_(j) can independently be selected from alkoxy, aryloxy,alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, cycloalkyl,ether, haloalkyl, heteroaryl, and heterocyclyl. R_(i) can be a hydrogen,but R_(j) cannot be hydrogen. The ester may be cyclic, for example thecarbon atom and R_(j), the oxygen atom and R_(i), or R_(i) and R_(j) maybe joined to form a 3- to 12-membered ring. Exemplary esters include,but are not limited to, alkyl esters wherein at least one of R_(i) orR_(j) is alkyl, such as —O—C(O)-alkyl, —C(O)—O-alkyl-, and-alkyl-C(O)—O-alkyl-. Exemplary esters also include aryl or heteroarylesters, e.g. wherein at least one of R_(i) or R_(j) is an aryl group,such as phenyl or tolyl, or a heteroaryl group, such as pyridine,pyridazine, pyrimidine or pyrazine, such as a nicotinate ester.Exemplary esters also include reverse esters having the structure—R_(j)C(O)O—, where the oxygen is bound to the parent molecule.Exemplary reverse esters include succinate, D-argininate, L-argininate,L-lysinate and D-lysinate. Esters also include carboxylic acidanhydrides and acid halides.

The term “ether” refers to the structure —R_(k)O—R_(i)—, where R_(k) andR_(i) can independently be alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, and ether. The ether can be attached to the parentmolecular group through R_(k) or R_(i). Exemplary ethers include, butare not limited to, alkoxyalkyl and alkoxyaryl groups. Ethers alsoincludes polyethers, e.g., where one or both of R_(k) and R_(i) areethers.

The terms “halo” or “halogen” or “hal” or “halide” as used herein referto F, Cl, Br, or I.

The term “haloalkyl” as used herein refers to an alkyl group substitutedwith one or more halogen atoms. “Haloalkyls” also encompass alkenyl oralkynyl groups substituted with one or more halogen atoms.

The terms “hydroxy” and “hydroxyl” as used herein refers to —OH.

The term “hydroxyalkyl” as used herein refers to a hydroxy attached toan alkyl group.

The term “hydroxyaryl” as used herein refers to a hydroxy attached to anaryl group.

The term “ketone” as used herein refers to the structure —C(O)—R_(m)(such as acetyl, —C(O)CH₃) or —R_(m)—C(O)—R_(n)—. The ketone can beattached to another group through R_(m) or R_(n). R_(m) or R_(n) can bealkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or aryl, or R_(m) orR_(n) can be joined to form, for example, a 3- to 12-membered ring.

The term “monoester” as used herein refers to an analogue of adicarboxylic acid wherein one of the carboxylic acids is functionalizedas an ester and the other carboxylic acid is a free carboxylic acid orsalt of a carboxylic acid. Examples of monoesters include, but are notlimited to, to monoesters of succinic acid, glutaric acid, adipic acid,suberic acid, sebacic acid, azelaic acid, oxalic and maleic acid.

The term “nitro” as used herein refers to —NO₂.

The term “nitrate” as used herein refers to NO³⁻.

The term “perfluoroalkyl” as used herein refers to an alkyl group inwhich all of the hydrogen atoms have been replaced by fluorine atoms.Exemplary perfluoroalkyl groups include, but are not limited to, C₁-C₅perfluoroalkyl, such as trifluoromethyl.

The term “perfluorocycloalkyl” as used herein refers to a cycloalkylgroup in which all of the hydrogen atoms have been replaced by fluorineatoms.

The term “perfluoroalkoxy” as used herein refers to an alkoxy group inwhich all of the hydrogen atoms have been replaced by fluorine atoms.

The term “phosphate” as used herein refers to the structure —OP(O)O₂ ²⁻,—R_(o)OP(O)O₂ ²⁻, —OP(O)(OR_(q))O⁻, or —R_(o)OP(O)(OR_(p))O⁻, whereinR_(o), R_(p) and R_(q) each independently can be alkyl, alkenyl,alkynyl, aryl, cycloalkyl, heterocyclyl, or hydrogen.

The term “sulfide” as used herein refers to the structure —R_(q)S—,where R_(q) can be alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,haloalkyl, heteroaryl, heterocyclyl. The sulfide may be cyclic, forexample, forming a 3 to 12-membered ring. The term “alkylsulfide” asused herein refers to an alkyl group attached to a sulfur atom.

The term “sulfinyl” as used herein refers to the structure —S(O)O—,—R_(r)S(O)O—, —R_(r)S(O)OR_(s)—, or —S(O)OR_(s)—, wherein R_(r) andR_(s) can be alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, haloalkyl,heteroaryl, heterocyclyl, hydroxyl. Exemplary sulfinyl groups include,but are not limited to, alkylsulfinyls wherein at least one of R_(r) orR_(s) is alkyl, alkenyl, or alkynyl.

The term “sulfonamide” as used herein refers to the structure—(R_(t))—N—S(O)₂—R_(v)— or —R_(t)(R_(u))N—S(O)₂—R_(v), where R_(t),R_(u), and R_(v) can be, for example, hydrogen, alkyl, alkenyl, alkynyl,aryl, cycloalkyl, and heterocyclyl. Exemplary sulfonamides includealkylsulfonam ides (e.g., where R_(v) is alkyl), arylsulfonamides (e.g.,where R_(v) is aryl), cycloalkyl sulfonamides (e.g., where R_(v) iscycloalkyl), and heterocyclyl sulfonamides (e.g., where R_(v) isheterocyclyl).

The term “sulfonate” as used herein refers to a salt or ester of asulfonic acid. The term “sulfonic acid” refers to R_(w)SO₃H, where R_(w)is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or heterocyclyl (e.g.,alkylsulfonyl). The term “sulfonyl” as used herein refers to thestructure R_(x)SO₂—, where R_(x) can be alkyl, alkenyl, alkynyl, aryl,cycloalkyl, and heterocyclyl (e.g., alkylsulfonyl). The term“alkylsulfonyl” as used herein refers to an alkyl group attached to asulfonyl group. “Alkylsulfonyl” groups can optionally contain alkenyl oralkynyl groups.

The term “sulfonate” as used herein refers R_(w)SO³⁻, where R_(w) isalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, hydroxyl,alkoxy, aroxy, or aralkoxy, where each of the alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, alkoxy, aroxy, or aralkoxy optionally issubstituted. Non-limiting examples include triflate (also known astrifluoromethanesulfonate, CF₃SO³⁻), benzenesulfonate, tosylate (alsoknown as toluenesulfonate), and the like.

The term “thioketone” refers to the structure —R_(y)—C(S)—R_(z)—. Theketone can be attached to another group through R_(y) or R. R_(y) orR_(z) can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or aryl,or R_(y) or R_(z) can be joined to form a ring, for example, a 3- to12-membered ring.

Each of the above groups may be optionally substituted. As used herein,the term “substituted” is contemplated to include all permissiblesubstituents of organic compounds, “permissible” being in the context ofthe chemical rules of valence known to those of ordinary skill in theart. It will be understood that “substituted” also includes that thesubstitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, etc. In some cases, “substituted” maygenerally refer to replacement of a hydrogen with a substituent asdescribed herein. However, “substituted,” as used herein, does notencompass replacement and/or alteration of a functional group by which amolecule is identified, e.g., such that the “substituted” functionalgroup becomes, through substitution, a different functional group. Forexample, a “substituted phenyl group” must still comprise the phenylmoiety and cannot be modified by substitution, in this definition, tobecome, e.g., a pyridine ring.

In a broad aspect, the permissible substituents include acyclic andcyclic, branched and unbranched, carbocyclic and heterocyclic, aromaticand nonaromatic substituents of organic compounds. Illustrativesubstituents include, for example, those described herein. Thepermissible substituents can be one or more and the same or differentfor appropriate organic compounds. For purposes of the presentteachings, the heteroatoms such as nitrogen may have hydrogensubstituents and/or any permissible substituents of organic compoundsdescribed herein which satisfy the valencies of the heteroatoms.

In various embodiments, the substituent is selected from alkoxy,aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate,sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone,each of which optionally is substituted with one or more suitablesubstituents. In some embodiments, the substituent is selected fromalkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, carboxy, cycloalkyl, ester, ether, formyl, haloalkyl,heteroaryl, heterocyclyl, ketone, phosphate, sulfide, sulfinyl,sulfonyl, sulfonic acid, sulfonamide, and thioketone, wherein each ofthe alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl,arylalkyl, carbamate, carboxy, cycloalkyl, ester, ether, formyl,haloalkyl, heteroaryl, heterocyclyl, ketone, phosphate, sulfide,sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone can befurther substituted with one or more suitable substituents.

Examples of substituents include, but are not limited to, halogen,azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl,amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate,carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido,ketone, aldehyde, thioketone, ester, heterocyclyl, —CN, aryl, aryloxy,perhaloalkoxy, aralkoxy, heteroaryl, heteroaryloxy, heteroarylalkyl,heteroaralkoxy, azido, alkylthio, oxo, acylalkyl, carboxy esters,carboxamido, acyloxy, aminoalkyl, alkylaminoaryl, alkylaryl,alkylaminoalkyl, alkoxyaryl, arylamino, aralkylamino, alkylsulfonyl,carboxamidoalkylaryl, carboxamidoaryl, hydroxyalkyl, haloalkyl,alkylaminoalkylcarboxy, aminocarboxamidoalkyl, cyano, alkoxyalkyl,perhaloalkyl, arylalkyloxyalkyl, and the like. In some embodiments, thesubstituent is selected from cyano, halogen, hydroxyl, and nitro.

As a non-limiting example, in various embodiments when one of the R_(a),R_(b), and R_(b′) in NR_(a)R_(b)R_(b′), referred to herein as an amineor amino, is selected from alkyl, alkenyl, alkynyl, cycloalkyl, andheterocyclyl, each of the alkyl, alkenyl, alkynyl, cycloalkyl, andheterocyclyl independently can be optionally substituted with one ormore substituents each independently selected from alkoxy, aryloxy,alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate,carboxy, cycloalkyl, ester, ether, formyl, haloalkyl, heteroaryl,heterocyclyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonicacid, sulfonamide, and thioketone, wherein each of the alkoxy, aryloxy,alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate,carboxy, cycloalkyl, ester, ether, formyl, haloalkyl, heteroaryl,heterocyclyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonicacid, sulfonamide, and thioketone can be further substituted with one ormore suitable substituents. In some embodiments when the amine is analkyl amine or a cycloalkylamine, the alkyl or the cycloalkyl can besubstituted with one or more substituents each independently selectedfrom alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl,arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl,halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro,phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, andthioketone. In certain embodiments when the amine is an alkyl amine or acycloalkylamine, the alkyl or the cycloalkyl can be substituted with oneor more substituents each independently selected from amino, carboxy,cyano, and hydroxyl. For example, the alkyl or the cycloalkyl in thealkyl amine or the cycloalkylamine is substituted with an amino group,forming a diamine.

As used herein, a “suitable substituent” refers to a group that does notnullify the synthetic or pharmaceutical utility of the compounds of theinvention or the intermediates useful for preparing them. Examples ofsuitable substituents include, but are not limited to: (C₁-C₂₂),(C₁-C₈), (C₁-C₆), or (C₁-C₄) alkyl, alkenyl or alkynyl; (C₆-C₂₂),(C₆-C₁₈), (C₆-C₁₄), or (C₆-C₁₀) aryl; (C₂-C₂₁), (C₂-C₁₇), (C₂-C₁₃), or(C₂-C₉) heteroaryl; (C₃-C₂₂), (C₃-C₁₂), or (C₃-C₈) cycloalkyl; (C₁-C₂₂),(C₁-C₈), (C₁-C₆), or (C₁-C₄) alkoxy; (C₆-C₂₂), (C₆-C₁₈), (C₆-C₁₄), or(C₆-C₁₀) aryloxy; —CN; —OH; oxo; halo; carboxy; amino, such as—NH((C₁-C₂₂), (C₁-C₈), (C₁-C₆), or (C₁-C₄) alkyl), —N((C₁-C₂₂), (C₁-C₈),(C₁-C₆), or (C₁-C₄) alkyl)₂, —NH((C₆)aryl), or —N((C₆-C₁₀) aryl)₂;formyl; ketones, such as —CO((C₁-C₂₂), (C₁-C₈), (C₁-C₆), or (C₁-C₄)alkyl), —CO(((C₆-C₁₀) aryl) esters, such as —CO₂((C₁-C₂₂), (C₁-C₈),(C₁-C₆), or (C₁-C₄) alkyl) and —CO₂((C₆-C₁₀) aryl). One of skill in artcan readily choose a suitable substituent based on the stability andpharmacological and synthetic activity of the compound of the invention.

The term “pharmaceutically acceptable counter ion” refers to apharmaceutically acceptable anion or cation. In various embodiments, thepharmaceutically acceptable counter ion is a pharmaceutically acceptableion. For example, the pharmaceutically acceptable counter ion isselected from citrate, matate, acetate, oxalate, chloride, bromide,iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate,isonicotinate, acetate, lactate, salicylate, tartrate, oleate, tannate,pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate,fumarate, gluconate, glucaronate, saccharate, formate, benzoate,glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)). In some embodiments, thepharmaceutically acceptable counter ion is selected from chloride,bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate,citrate, matate, acetate, oxalate, acetate, and lactate. In particularembodiments, the pharmaceutically acceptable counter ion is selectedfrom chloride, bromide, iodide, nitrate, sulfate, bisulfate, andphosphate.

The term “pharmaceutically acceptable salt(s)” refers to salts of acidicor basic groups that may be present in compounds used in the presentteachings. Compounds included in the present teachings that are basic innature are capable of forming a wide variety of salts with variousinorganic and organic acids. The acids that may be used to preparepharmaceutically acceptable acid addition salts of such basic compoundsare those that form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, including but notlimited to sulfate, citrate, matate, acetate, oxalate, chloride,bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate,isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate,tannate, pantothenate, bitartrate, ascorbate, succinate, maleate,gentisinate, fumarate, gluconate, glucaronate, saccharate, formate,benzoate, glutamate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds includedin the present teachings that include an amino moiety may formpharmaceutically acceptable salts with various amino acids, in additionto the acids mentioned above. Compounds included in the presentteachings, that are acidic in nature are capable of forming base saltswith various pharmacologically acceptable cations. Examples of suchsalts include alkali metal or alkaline earth metal salts and,particularly, calcium, magnesium, sodium, lithium, zinc, potassium, andiron salts.

In addition, if the compounds described herein are obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid salt. Conversely, if the product is a free base, an additionsalt, particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds. Thoseskilled in the art will recognize various synthetic methodologies thatmay be used to prepare non-toxic pharmaceutically acceptable additionsalts.

A pharmaceutically acceptable salt can be derived from an acid selectedfrom 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid,2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoicacid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid,aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid,camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid(hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamicacid, citric acid, cyclamic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaricacid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid,glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid,glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid,isethionic, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonicacid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmiticacid, pamoic acid, pantothenic, phosphoric acid, proprionic acid,pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinicacid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonicacid, trifluoroacetic, and undecylenic acid.

Unless otherwise specified, the chemical groups include theircorresponding monovalent, divalent, trivalent, and tetravalent groups.For example, methyl includes monovalent methyl (—CH₃), divalent methyl(—CH₂—, methylyl), trivalent methyl

and tetravalent methyl

Unless otherwise specified, all numbers expressing quantities ofingredients, reaction conditions, and other properties or parametersused in the specification and claims are to be understood as beingmodified in all instances by the term “about.” Accordingly, unlessotherwise indicated, it should be understood that the numericalparameters set forth in the following specification and attached claimsare approximations. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of theclaims, numerical parameters should be read in light of the number ofreported significant digits and the application of ordinary roundingtechniques. For example, the term “about” can encompass variations of±10%, ±5%, ±2%, ±1%, ±0.5%, or ±0.1% of the numerical value of thenumber which the term “about” modifies. In various embodiments, the term“about” encompasses variations of ±5%, ±2%, ±1%, or ±0.5% of thenumerical value of the number. In some embodiments, the term “about”encompasses variations of ±5%, ±2%, or ±1% of the numerical value of thenumber. In certain embodiments, the term “about” encompasses variationsof ±5% of the numerical value of the number. In certain embodiments, theterm “about” encompasses variations of ±2% of the numerical value of thenumber. In certain embodiments, the term “about” encompasses variationsof ±1% of the numerical value of the number.

All numerical ranges herein include all numerical values and ranges ofall numerical values within the recited range of numerical values. As anon-limiting example, (C₁-C₆) alkyls also include any one of C₁, C₂, C₃,C₄, C₅, C₆, (C₁-C₂), (C₁-C₃), (C₁-C₄), (C₁-C₅), (C₂-C₃), (C₂-C₄),(C₂-C₅), (C₂-C₆), (C₃-C₄), (C₃-C₅), (C₃-C₆), (C₄-C₅), (C₄-C₆), and(C₅-C₆) alkyls.

Further, while the numerical ranges and parameters setting forth thebroad scope of the disclosure are approximations as discussed above, thenumerical values set forth in the Examples section are reported asprecisely as possible. It should be understood, however, that suchnumerical values inherently contain certain errors resulting from themeasurement equipment and/or measurement technique.

The term “hydrophilic,” as used herein, generally describes the propertyof attracting water and the term “hydrophobic,” as used herein,generally describes the property of repelling water. Thus, a hydrophiliccompound (e.g., small molecule or polymer) is one generally thatattracts water and a hydrophobic compound (e.g., small molecule orpolymer) is one that generally repels water. A hydrophilic or ahydrophobic compound can be identified, for example, by preparing asample of the compound and measuring its contact angle with water. Insome cases, the hydrophilicity of two or more compounds may be measuredrelative to each other, i.e., a first compound may be more hydrophilicthan a second compound.

Compounds

The present teachings generally provide compounds, compositions, andmethods of using the compounds or compositions.

In various embodiments, each of the compounds of the present teachingshas Formula I:

-   -   or a pharmaceutically acceptable salt thereof,    -   wherein:    -   two of R¹, R², R³, and R⁴ each independently is a halide or a        carboxylate; the remaining two of R¹, R², R³, and R⁴ each        independently is an amine; and        -   X is absent, C(R⁵)₂, or NR⁵,        -   Y is absent, C(R⁶)₂, or NR⁶,        -   R⁵ and R⁶ independently at each occurrence is selected from            hydrogen, alkyl, alkenyl, alkynyl, ether, amine, and            carboxylate, wherein each of the alkyl, the alkenyl, the            alkynyl, the ether, and the amine groups optionally is            substituted with one or more groups, each independently            selected from halogen, hydroxyl, ether, alkoxy, and amine,            wherein each of the ether, the alkoxy, or the amine is            optionally substituted with one or more suitable            substituents; and    -   at least one of R¹, R², R³, R⁴, R⁵, and R⁶ comprises a polar        moiety.

In some embodiments, at least two of R₁, R₂, R₃, R₄, R₅, and R₆ eachcomprises a polar moiety. In certain embodiments, two of R¹, R², R³, andR⁴ each comprise a polar moiety. For example, two of R¹, R², R³, and R⁴,joined together, can comprise a polar moiety. In certain embodiments, atleast one of R⁵ and R⁶ comprises a polar moiety. For example, each of R⁵and R⁶ can comprise a polar moiety. A polar moiety in variousembodiments can be ether, amino, or carboxylate, each of which isoptionally substituted with one or more suitable substituents. In someembodiments, the polar moiety is a dicarboxylic acid, a carboxylate, apolyether, an amine, or a diamine, each of which optionally issubstituted with a suitable substituent. In certain embodiments, thepolar moiety is a dicarboxylic acid, a carboxylate, a polyether, or adiamine. In particular embodiments, the polar moiety is a dicarboxylicacid. In particular embodiments, the polar moiety is a carboxylate. Inparticular embodiments, the polar moiety is a polyether.

In various embodiments, at least one of R¹, R², R³, and R⁴ is a halide.For example, at least one of R¹, R², R³, and R⁴ is Cl. In someembodiments, two of R¹, R², R³, and R⁴ each is a halide. In someembodiments, two of R¹, R², R³, and R⁴ each is Cl.

In various embodiments, at least one of R¹, R², R³, and R⁴ is—O(C═O)R^(a), and R^(a) is hydrogen, alkyl, aryl, arylalkyl, orcycloalkyl, wherein each of the alkyl, aryl, arylalkyl, and cycloalkylis optionally substituted with one or more suitable substituents. Insome embodiments, two of R¹, R², R³, and R⁴ each is —O(C═O)R^(a), andR^(a) is as defined herein. In some embodiments, two of R¹, R², R³, andR⁴ form a bidentate ligand as described herein.

In various embodiments, at least one of R¹, R², R³, and R⁴ is an amine.In some embodiments, two of R¹, R², R³, and R⁴ each is an amine. In someembodiments, two of R¹, R², R³, and R⁴ form a bidentate ligand asdescribed herein.

Some embodiments comprise compounds having two ligands (e.g., R¹, R²,R³, and R⁴) positioned in a cis configuration, i.e., the compound may bea cis isomer. However, it should be understood that compounds of thepresent teachings may also have two ligands (e.g., R¹, R², R³, and R⁴)positioned in a trans configuration, i.e., the compound may be a transisomer. Those of ordinary skill in the art would understand the meaningof these terms.

A “polar moiety”, as used herein, refers to any chemical group in whichthe distribution of electrons is uneven enabling it to take part inelectrostatic interactions. For example, a chemical group comprisingelectronegative atoms may give rise to unequal sharing of electrons inthe bonds and thereby rendering the chemical group a polar moiety.Examples of polar moieties include, but not limited to, ether groups,amine groups, halide groups, carboxic acid groups, carboxylate groups,ester groups, thiol groups, and so on.

In some embodiments, the compounds of the present invention are polar.In some embodiments, the compounds of the present teachings have alogarithm of partition-coefficient value (log P) less than about 2. Insome embodiments, the compounds of the present teachings have a log Pless than about 1.7. In some embodiments, the compounds of the presentteachings have a log P less than about 1.3. In some embodiments, thecompounds of the present teachings have a log P less than about 1.1. Asused herein, partition coefficient P measures the tendency of thecompound to partition between lipophilic organic phase (immisciple withwater) and polar aqueous phase. Log P may be measured using any knownmethod. As a non-limiting example, log P may be measured using a“shake-flask” method, wherein the compound is incubated in two-phasesystem under shaking, and samples collected from both phases afterequilibration are analyzed with using analytical methods such as HPLC,LC/MS, or by spectrophotometer. As another non-limiting example, log Pmay be measured based on chromatographic retention times, e.g., measuredusing an HPLC retention time method, under validated conditions usingreference compounds with reported log P. In some embodiments, thecompounds of the present invention are charged. In some embodiments, thecompounds of the present invention are not charged.

In various embodiments, the compounds of the present teachings each hasFormula Ia:

wherein X, Y, R¹, R², R³, R⁴, R⁵, and R⁶ are as defined herein.

In some embodiments, at least one of R³ and R⁴ is a halide. In certainembodiments, both R³ and R⁴ are Cl.

In some embodiments, at least one of R³ and R⁴ is —O(C═O)R^(a), andR^(a) is hydrogen, alkyl, aryl, arylalkyl, or cycloalkyl, wherein eachof the alkyl, the aryl, the arylalkyl, and the cycloalkyl is optionallysubstituted with one or more suitable substituents. In some embodiments,both R³ and R⁴ are —O(C═O)R^(a), and R^(a) is hydrogen, alkyl, aryl,arylalkyl, or cycloalkyl, wherein each of the alkyl, the aryl, thearylalkyl, and the cycloalkyl is optionally substituted with one or moresuitable substituents. In certain embodiments, R³ and R⁴, joinedtogether, form a bidentate ligand as described herein.

In some embodiments, at least one of R¹ and R² is an amine. For example,at least one of R¹ and R² is an alkylamine, alkenylamine, alkynylamine,arylamine, arylalkylamine, cycloalkylamine, heterocycloalkylamine, orheteroarylamine. In certain embodiments, R¹ and R², joined together,form a bidentate ligand as described herein.

In some embodiments, two ligands may be joined together to form abidentate ligand. As will be known to those of ordinary skill in theart, a bidentate ligand, as used herein, when bound to a metal center,forms a metallacycle structure with the metal center, also known as achelate ring. Bidentate ligands include species that have at least twosites capable of binding to a metal center. For example, a bidentateligand may comprise at least two heteroatoms that coordinate the metalcenter, or a heteroatom and an anionic carbon atom that coordinate themetal center.

Examples of bidentate ligands suitable for use in the present teachingsinclude diamines, including ethylenediamine, cyclohexyldiamine,cyclobutanediyldimethanamine, and the like, or dicarboxylic acids. Insome embodiments, R¹ and R² are joined together to form ethylenediamine,cyclobutane-1,2-diyldimethanamine, cyclohexane-1,2-diamine, or the like.In certain embodiments, R¹ and R² are joined together to formcyclobutane-1,2-diyldimethanamine or cyclohexane-1,2-diamine. In certainembodiments, R¹ and R² are joined together to formcyclohexane-1,2-diamine.

In various embodiments, the compounds of the present teachings each hasFormula II:

-   -   wherein R¹, R², R³, R⁴, R⁵, and R⁶ are as defined herein and    -   at least one of R¹, R², R³, R⁴, R⁵, and R⁶ comprises a polar        moiety.

In various embodiments, the compounds of the present teachings each hasFormula IIIa:

-   -   wherein R⁵ and R⁶ are as defined herein and    -   at least one of R⁵ and R⁶ comprises a polar moiety.

In some embodiments, R³ and R⁴ are joined together to form adicarboxylic acid. For example, the dicarboxylic acid can be oxalicacid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelicacid, cyclobutane dicarboxylic acid, cyclopentane dicarboxylic acid,cyclohexane dicarboxylic acid, cycloheptane dicarboxylic acid, or thelike. In certain embodiments, R³ and R⁴ are joined together to formoxalic acid.

In various embodiments, the compounds of the present teachings each hasFormula IIIb:

-   -   wherein R⁵ and R⁶ are as defined herein and    -   at least one of R⁵ and R⁶ comprises a polar moiety.

In various embodiments, X or Y is absent.

In various embodiments, X is C(R⁵)₂, wherein each R⁵ independently isdefined herein. In various embodiments, X is NR⁵, where R⁵ is as definedherein.

In various embodiments, Y is C(R⁶)₂, wherein each R⁶ independently isdefined herein. In various embodiments, Y is NR⁶, where R⁶ is as definedherein.

In various embodiments, R⁵ and R⁶ at each occurrence is hydrogen oralkyl, optionally substituted with one or more groups, eachindependently selected from halogen, hydroxyl, ether, alkoxy, and amine,wherein each of the ether, the alkoxy, or the amine is optionallysubstituted with one or more suitable substituents. In some embodiments,R⁵ or R⁶ at least at one occurrence is hydrogen or CH₃.

In particular embodiments, X is CH₂ or C(CH₃)₂. In particularembodiments, X is NH.

In particular embodiments, Y is CH₂ or C(CH₃)₂. In particularembodiments, Y is NH.

In various embodiments, X, Y, R⁵ and R⁶ are different. For example, thecompound of the present teachings is:

In various embodiments, R⁵ and R⁶ can be the same. For example, thecompound of the present teachings can be selected from:

As described herein, some compounds of the present teachings may beprovided as a salt comprising a charged platinum complex and a counterion, including a pharmaceutically acceptable counter ion. The counterion may be a weak or non-nucleophilic stabilizing ion, having a chargeof (−1), (−2), (−3), (+1), (+2), (+3), etc. In some embodiments, thecounter ion has a charge of (−1). In other embodiments, the counter ionhas a charge of (−2). In some embodiments, the counter ion has a chargeof (+1). In other embodiments, the counter ion has a charge of (+2).

Formulation, Delivery, Administration, and Dosing

The present teachings further comprise compositions (includingpharmaceutical compositions) each comprising one or more of thecompounds as described herein, and at least one pharmaceuticallyacceptable excipient.

In some embodiments, compositions are administered to humans, humanpatients or subjects. For the purposes of the present disclosure, thephrase “active ingredient” generally refers to the compounds to bedelivered as described herein.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, it will be understood by theskilled artisan that such compositions are generally suitable foradministration to any other animal, e.g., to non-human animals, e.g.non-human mammals. Modification of pharmaceutical compositions suitablefor administration to humans in order to render the compositionssuitable for administration to various animals is well understood, andthe ordinarily skilled veterinary pharmacologist can design and/orperform such modification with merely ordinary, if any, experimentation.Subjects to which administration of the pharmaceutical compositions iscontemplated include, but are not limited to, humans and/or otherprimates; mammals, including commercially relevant mammals such ascattle, pigs, horses, sheep, cats, dogs, mice, and/or rats; and/orbirds, including commercially relevant birds such as poultry, chickens,ducks, geese, and/or turkeys.

Formulations of the pharmaceutical compositions described herein may beprepared by any method known or hereafter developed in the art ofpharmacology. In general, such preparatory methods include the step ofbringing the active ingredient into association with an excipient and/orone or more other accessory ingredients, and then, if necessary and/ordesirable, dividing, shaping and/or packaging the product into a desiredsingle- or multi-dose unit.

A pharmaceutical composition in accordance with the invention may beprepared, packaged, and/or sold in bulk, as a single unit dose, and/oras a plurality of single unit doses. As used herein, a “unit dose” isdiscrete amount of the pharmaceutical composition comprising apredetermined amount of the active ingredient. The amount of the activeingredient is generally equal to the dosage of the active ingredientwhich would be administered to a subject and/or a convenient fraction ofsuch a dosage such as, for example, one-half or one-third of such adosage.

Relative amounts of the active ingredient, the pharmaceuticallyacceptable excipient, and/or any additional ingredients in apharmaceutical composition in accordance with the invention will vary,depending upon the identity, size, and/or condition of the subjecttreated and further depending upon the route by which the composition isto be administered. By way of example, the composition may comprisebetween 0.1% and 100%, e.g., between 0.5 and 50%, between 1-30%, between5-80%, at least 80% (w/w) active ingredient.

The compounds of the present invention can be formulated using one ormore excipients to: (1) increase stability; (2) permit the sustained ordelayed release (e.g., from a depot formulation of the compounds of thepresent invention); (3) alter the biodistribution (e.g., target thecompounds of the present invention to specific tissues or cell types);(4) alter the release profile of the compounds of the invention in vivo.Non-limiting examples of the excipients include any and all solvents,dispersion media, diluents, or other liquid vehicles, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, and preservatives. Excipients of the presentinvention may also include, without limitation, lipidoids, liposomes,lipid nanoparticles, polymers, lipoplexes, core-shell nanoparticles,peptides, proteins, hyaluronidase, nanoparticle mimics and combinationsthereof. Accordingly, the formulations of the invention may include oneor more excipients, each in an amount that together increases thestability of the compounds of the present invention.

Excipients

Pharmaceutical formulations may additionally comprise a pharmaceuticallyacceptable excipient, which, as used herein, includes any and allsolvents, dispersion media, diluents, or other liquid vehicles,dispersion or suspension aids, surface active agents, isotonic agents,thickening or emulsifying agents, preservatives, solid binders,lubricants and the like, as suited to the particular dosage formdesired. Remington's The Science and Practice of Pharmacy, 21st Edition,A. R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2006;incorporated herein by reference in its entirety) discloses variousexcipients used in formulating pharmaceutical compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional excipient medium is incompatible with a substance or itsderivatives, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutical composition, its use is contemplatedto be within the scope of this invention.

In some embodiments, a pharmaceutically acceptable excipient is at least95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%pure. In some embodiments, an excipient is approved for use in humansand for veterinary use. In some embodiments, an excipient is approved byUnited States Food and Drug Administration. In some embodiments, anexcipient is pharmaceutical grade. In some embodiments, an excipientmeets the standards of the United States Pharmacopoeia (USP), theEuropean Pharmacopoeia (EP), the British Pharmacopoeia, and/or theInternational Pharmacopoeia.

Pharmaceutically acceptable excipients used in the manufacture ofpharmaceutical compositions include, but are not limited to, inertdiluents, dispersing and/or granulating agents, surface active agentsand/or emulsifiers, disintegrating agents, binding agents,preservatives, buffering agents, lubricating agents, and/or oils. Suchexcipients may optionally be included in pharmaceutical compositions.

Exemplary diluents include, but are not limited to, calcium carbonate,sodium carbonate, calcium phosphate, dicalcium phosphate, calciumsulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose,cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol,inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc.,and/or combinations thereof.

Exemplary granulating and/or dispersing agents include, but are notlimited to, potato starch, corn starch, tapioca starch, sodium starchglycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite,cellulose and wood products, natural sponge, cation-exchange resins,calcium carbonate, silicates, sodium carbonate, cross-linkedpoly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch(sodium starch glycolate), carboxymethyl cellulose, cross-linked sodiumcarboxymethyl cellulose (croscarmellose), methylcellulose,pregelatinized starch (starch 1500), microcrystalline starch, waterinsoluble starch, calcium carboxymethyl cellulose, magnesium aluminumsilicate (VEEGUM®), sodium lauryl sulfate, quaternary ammoniumcompounds, etc., and/or combinations thereof.

Exemplary surface active agents and/or emulsifiers include, but are notlimited to, natural emulsifiers (e.g. acacia, agar, alginic acid, sodiumalginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin,egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidalclays (e.g. bentonite [aluminum silicate] and VEEGUM® [magnesiumaluminum silicate]), long chain amino acid derivatives, high molecularweight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol,triacetin monostearate, ethylene glycol distearate, glycerylmonostearate, and propylene glycol monostearate, polyvinyl alcohol),carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acidpolymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives(e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylenesorbitan monolaurate [TWEEN®20], polyoxyethylene sorbitan [TWEENn®60],polyoxyethylene sorbitan monooleate [TWEEN®80], sorbitan monopalmitate[SPAN®40], sorbitan monostearate [SPAN®60], sorbitan tristearate[SPAN®65], glyceryl monooleate, sorbitan monooleate [SPAN®80]),polyoxyethylene esters (e.g. polyoxyethylene monostearate [MYRJ®45],polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil,polyoxymethylene stearate, and SOLUTOL®), sucrose fatty acid esters,polyethylene glycol fatty acid esters (e.g. CREMOPHOR®), polyoxyethyleneethers, (e.g. polyoxyethylene lauryl ether [BRIJ®30]),poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamineoleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyllaurate, sodium lauryl sulfate, PLUORINC®F 68, POLOXAMER®188,cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride,docusate sodium, etc. and/or combinations thereof.

Exemplary binding agents include, but are not limited to, starch (e.g.cornstarch and starch paste); gelatin; sugars (e.g. sucrose, glucose,dextrose, dextrin, molasses, lactose, lactitol, mannitol,); natural andsynthetic gums (e.g. acacia, sodium alginate, extract of Irish moss,panwar gum, ghatti gum, mucilage of isapol husks,carboxymethylcellulose, methylcellulose, ethylcellulose,hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate,poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), andlarch arabogalactan); alginates; polyethylene oxide; polyethyleneglycol; inorganic calcium salts; silicic acid; polymethacrylates; waxes;water; alcohol; etc.; and combinations thereof.

Exemplary preservatives may include, but are not limited to,antioxidants, chelating agents, antimicrobial preservatives, antifungalpreservatives, alcohol preservatives, acidic preservatives, and/or otherpreservatives. Exemplary antioxidants include, but are not limited to,alpha tocopherol, ascorbic acid, acorbyl palmitate, butylatedhydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassiummetabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodiumbisulfite, sodium metabisulfite, and/or sodium sulfite. Exemplarychelating agents include ethylenediaminetetraacetic acid (EDTA), citricacid monohydrate, disodium edetate, dipotassium edetate, edetic acid,fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaricacid, and/or trisodium edetate. Exemplary antimicrobial preservativesinclude, but are not limited to, benzalkonium chloride, benzethoniumchloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride,chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethylalcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol,phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and/orthimerosal. Exemplary antifungal preservatives include, but are notlimited to, butyl paraben, methyl paraben, ethyl paraben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate,potassium sorbate, sodium benzoate, sodium propionate, and/or sorbicacid. Exemplary alcohol preservatives include, but are not limited to,ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol,chlorobutanol, hydroxybenzoate, and/or phenylethyl alcohol. Exemplaryacidic preservatives include, but are not limited to, vitamin A, vitaminC, vitamin E, beta-carotene, citric acid, acetic acid, dehydroaceticacid, ascorbic acid, sorbic acid, and/or phytic acid. Otherpreservatives include, but are not limited to, tocopherol, tocopherolacetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA),butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate(SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodiummetabisulfite, potassium sulfite, potassium metabisulfite, GLYDANTPLUS®, PHENONIP®, methylparaben, GERMALL®115, GERMABEN®II, NEOLONE™KATHON™, and/or EUXYL®.

Exemplary buffering agents include, but are not limited to, citratebuffer solutions, acetate buffer solutions, phosphate buffer solutions,ammonium chloride, calcium carbonate, calcium chloride, calcium citrate,calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconicacid, calcium glycerophosphate, calcium lactate, propanoic acid, calciumlevulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid,tribasic calcium phosphate, calcium hydroxide phosphate, potassiumacetate, potassium chloride, potassium gluconate, potassium mixtures,dibasic potassium phosphate, monobasic potassium phosphate, potassiumphosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride,sodium citrate, sodium lactate, dibasic sodium phosphate, monobasicsodium phosphate, sodium phosphate mixtures, tromethamine, magnesiumhydroxide, aluminum hydroxide, alginic acid, pyrogen-free water,isotonic saline, Ringer's solution, ethyl alcohol, etc., and/orcombinations thereof.

Exemplary lubricating agents include, but are not limited to, magnesiumstearate, calcium stearate, stearic acid, silica, talc, malt, glycerylbehanate, hydrogenated vegetable oils, polyethylene glycol, sodiumbenzoate, sodium acetate, sodium chloride, leucine, magnesium laurylsulfate, sodium lauryl sulfate, etc., and combinations thereof.

Exemplary oils include, but are not limited to, almond, apricot kernel,avocado, babassu, bergamot, black current seed, borage, cade, camomile,canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, codliver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose,fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop,isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon,litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink,nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel,peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary,safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, sheabutter, silicone, soybean, sunflower, tea tree, thistle, tsubaki,vetiver, walnut, and wheat germ oils. Exemplary oils include, but arenot limited to, butyl stearate, caprylic triglyceride, caprictriglyceride, cyclomethicone, diethyl sebacate, dimethicone 360,isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol,silicone oil, and/or combinations thereof.

Excipients such as cocoa butter and suppository waxes, coloring agents,coating agents, sweetening, flavoring, and/or perfuming agents can bepresent in the composition, according to the judgment of the formulator.

Administration

The compounds of the present invention may be administered by any routewhich results in a therapeutically effective outcome. These include, butare not limited to enteral, gastroenteral, epidural, oral, transdermal,epidural (peridural), intracerebral (into the cerebrum),intracerebroventricular (into the cerebral ventricles), epicutaneous(application onto the skin), intradermal, (into the skin itself),subcutaneous (under the skin), nasal administration (through the nose),intravenous (into a vein), intraarterial (into an artery), intramuscular(into a muscle), intracardiac (into the heart), intraosseous infusion(into the bone marrow), intrathecal (into the spinal canal),intraperitoneal, (infusion or injection into the peritoneum),intravesical infusion, intravitreal, (through the eye), intracavernousinjection, (into the base of the penis), intravaginal administration,intrauterine, extra-amniotic administration, transdermal (diffusionthrough the intact skin for systemic distribution), transmucosal(diffusion through a mucous membrane), insufflation (snorting),sublingual, sublabial, enema, eye drops (onto the conjunctiva), or inear drops. In specific embodiments, compositions may be administered ina way which allows them cross the blood-brain barrier, vascular barrier,or other epithelial barrier.

Dosing

The present invention provides methods comprising administering thecompounds of the present invention to a subject in need thereof.Compounds as described herein may be administered to a subject using anyamount and any route of administration effective for preventing ortreating or imaging a disease, disorder, and/or condition (e.g., adisease, disorder, and/or condition relating to working memorydeficits). The exact amount required will vary from subject to subject,depending on the species, age, and general condition of the subject, theseverity of the disease, the particular composition, its mode ofadministration, its mode of activity, and the like.

Compositions in accordance with the invention are typically formulatedin dosage unit form for ease of administration and uniformity of dosage.It will be understood, however, that the total daily usage of thecompositions of the present invention may be decided by the attendingphysician within the scope of sound medical judgment. The specifictherapeutically effective, prophylactically effective, or appropriateimaging dose level for any particular patient will depend upon a varietyof factors including the disorder being treated and the severity of thedisorder; the activity of the specific compound employed; the specificcomposition employed; the age, body weight, general health, sex and dietof the patient; the time of administration, route of administration, andrate of excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidental with the specificcompound employed; and like factors well known in the medical arts.

In some embodiments, compositions in accordance with the presentinvention may be administered at dosage levels sufficient to deliverfrom about 0.0001 mg/kg to about 100 mg/kg, from about 0.001 mg/kg toabout 0.05 mg/kg, from about 0.005 mg/kg to about 0.05 mg/kg, from about0.001 mg/kg to about 0.005 mg/kg, from about 0.05 mg/kg to about 0.5mg/kg, from about 0.01 mg/kg to about 50 mg/kg, from about 0.1 mg/kg toabout 40 mg/kg, from about 0.5 mg/kg to about 30 mg/kg, from about 0.01mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, or fromabout 1 mg/kg to about 25 mg/kg, of subject body weight per day, one ormore times a day, to obtain the desired therapeutic, diagnostic,prophylactic, or imaging effect. The desired dosage may be deliveredthree times a day, two times a day, once a day, every other day, everythird day, every week, every two weeks, every three weeks, or every fourweeks. In some embodiments, the desired dosage may be delivered usingmultiple administrations (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or moreadministrations). When multiple administrations are employed, splitdosing regimens such as those described herein may be used.

As used herein, a “split dose” is the division of single unit dose ortotal daily dose into two or more doses, e.g, two or moreadministrations of the single unit dose. As used herein, a “single unitdose” is a dose of any therapeutic administered in one dose/at onetime/single route/single point of contact, i.e., single administrationevent. As used herein, a “total daily dose” is an amount given orprescribed in 24 hr period. It may be administered as a single unitdose. In one embodiment, the compounds of the present invention areadministered to a subject in split doses. The compounds may beformulated in buffer only or in a formulation described herein.

Dosage Forms

A pharmaceutical composition described herein can be formulated into adosage form described herein, such as a topical, intranasal,intratracheal, or injectable (e.g., intravenous, intraocular,intravitreal, intramuscular, intracardiac, intraperitoneal,subcutaneous).

Liquid Dosage Forms

Liquid dosage forms for parenteral administration include, but are notlimited to, pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups, and/or elixirs. In addition to activeingredients, liquid dosage forms may comprise inert diluents commonlyused in the art including, but not limited to, water or other solvents,solubilizing agents and emulsifiers such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils(in particular, cottonseed, groundnut, corn, germ, olive, castor, andsesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycolsand fatty acid esters of sorbitan, and mixtures thereof. In certainembodiments for parenteral administration, compositions may be mixedwith solubilizing agents such as CREMOPHOR®, alcohols, oils, modifiedoils, glycols, polysorbates, cyclodextrins, polymers, and/orcombinations thereof.

Injectable

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known art andmay include suitable dispersing agents, wetting agents, and/orsuspending agents. Sterile injectable preparations may be sterileinjectable solutions, suspensions, and/or emulsions in nontoxicparenterally acceptable diluents and/or solvents, for example, asolution in 1,3-butanediol. Among the acceptable vehicles and solventsthat may be employed include, but are not limited to, water, Ringer'ssolution, U.S.P., and isotonic sodium chloride solution. Sterile, fixedoils are conventionally employed as a solvent or suspending medium. Forthis purpose any bland fixed oil can be employed including syntheticmono- or diglycerides. Fatty acids such as oleic acid can be used in thepreparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, and/or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of an active ingredient, it may bedesirable to slow the absorption of the active ingredient fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compounds thendepends upon its rate of dissolution which, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound may be accomplished by dissolvingor suspending the compounds in an oil vehicle. Injectable depot formsare made by forming microencapsule matrices of the compounds of thepresent invention in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of the compounds ofthe present invention to polymer and the nature of the particularpolymer employed, the rate of compound release can be controlled.Examples of other biodegradable polymers include, but are not limitedto, poly(orthoesters) and poly(anhydrides). Depot injectableformulations may be prepared by entrapping the compounds of the presentinvention in liposomes or microemulsions which are compatible with bodytissues.

Pulmonary

Formulations described herein as being useful for pulmonary delivery mayalso be used for intranasal delivery of a pharmaceutical composition.Another formulation suitable for intranasal administration may be acoarse powder comprising the active ingredient and having an averageparticle from about 0.2 um to 500 um. Such a formulation may beadministered in the manner in which snuff is taken, i.e. by rapidinhalation through the nasal passage from a container of the powder heldclose to the nose.

Formulations suitable for nasal administration may, for example,comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) ofactive ingredient, and may comprise one or more of the additionalingredients described herein. A pharmaceutical composition may beprepared, packaged, and/or sold in a formulation suitable for buccaladministration. Such formulations may, for example, be in the form oftablets and/or lozenges made using conventional methods, and may, forexample, contain about 0.1% to 20% (w/w) active ingredient, where thebalance may comprise an orally dissolvable and/or degradable compositionand, optionally, one or more of the additional ingredients describedherein. Alternately, formulations suitable for buccal administration maycomprise a powder and/or an aerosolized and/or atomized solution and/orsuspension comprising active ingredient. Such powdered, aerosolized,and/or aerosolized formulations, when dispersed, may have an averageparticle and/or droplet size in the range from about 0.1 nm to about 200nm, and may further comprise one or more of any additional ingredientsdescribed herein.

General considerations in the formulation and/or manufacture ofpharmaceutical agents may be found, for example, in Remington: TheScience and Practice of Pharmacy 21st ed., Lippincott Williams &Wilkins, 2005 (incorporated herein by reference in its entirety).

Coatings or Shells

Solid dosage forms of tablets, dragees, capsules, pills, and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well known in the pharmaceutical formulating art. Theymay optionally comprise opacifying agents and can be of a compositionthat they release the active ingredient(s) only, or preferentially, in acertain part of the intestinal tract, optionally, in a delayed manner.Examples of embedding compositions which can be used include polymericsubstances and waxes. Solid compositions of a similar type may beemployed as fillers in soft and hard-filled gelatin capsules using suchexcipients as lactose or milk sugar as well as high molecular weightpolyethylene glycols and the like.

Methods of Using the Compounds and Compositions

These and other embodiments of the present teachings may also involvepromotion of the treatment of cancer or tumor according to any of thetechniques and compositions and combinations of compositions describedherein.

In various embodiments, methods for treating a subject having a cancerare provided, wherein the method comprises administering atherapeutically-effective amount of a compound, as described herein, toa subject having a cancer, suspected of having cancer, or having apredisposition to a cancer. According to the present invention, cancerembraces any disease or malady characterized by uncontrolled cellproliferation, e.g., hyperproliferation. Cancers may be characterized bytumors, e.g., solid tumors or any neoplasm. In some embodiments, thesubject may be otherwise free of indications for treatment with saidcompound. In some embodiments, methods include use of cancer cells,including but not limited to mammalian cancer cells. In some instances,the mammalian cancer cells are human cancer cells.

In some embodiments, the compounds of the present teachings can inhibitgrowth of a cancer and/or tumor. They may also reduce cellproliferation, invasiveness, and/or metastasis, thereby rendering themuseful for treating a cancer.

In some embodiments, the compounds of the present teachings may be usedto prevent the growth of a tumor or cancer, and/or to prevent themetastasis of a tumor or cancer. In some embodiments, compositions ofthe present teachings may be used to shrink or destroy a cancer.

In some embodiments, a compound provided herein is useful for inhibitingproliferation of a cancer cell. In some embodiments a compound providedherein is useful for inducing cell death of a cancer cell or bothinhibiting proliferation or inducing cell death of a cancer cell.

The cancers treatable by methods of the present teachings generallyoccur in mammals. Mammals include, for example, humans and non-humanprimates, as well as pet or companion animals, such as dogs and cats,laboratory animals, such as rats, mice and rabbits, and farm animals,such as horses, pigs, sheep, and cattle. In various embodiments, thecancer is lung cancer, breast cancer, colorectal cancer, ovarian cancer,bladder cancer, prostate cancer, cervical cancer, renal cancer,leukemia, central nervous system cancers, myeloma, and melanoma. In someembodiments, the cancer is lung cancer. In certain embodiments, thecancer is human lung carcinoma and/or normal lung fibroblast.

In some embodiments, the compounds of the present invention areeffective for inhibiting tumor growth, whether measured as a net valueof size (weight, surface area or volume) or as a rate over time, inmultiple types of tumors.

In some embodiments, the size of a tumor is reduced by 60% or more.

In some embodiments, the size of a tumor is reduced by at least 20%, atleast 30%, at least 40%, at least 50%, at least 60%, at least 70%, atleast 80%, at least 90%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, at least 100%, by a measure of weight, and/orarea and/or volume.

In some embodiments, the RECIST (Response Evaluation Criteria In SolidTumors) criteria are used to characterize the effects of the compoundsof the invention on solid tumors. The guidelines for gauging tumors wereupdated and published in the European Journal of Cancer (EJC) in January2009 (Eisenhauer, et al., European Journal of Cancer: 45 (2009)228-247), the contents of which are incorporated herein by reference intheir entirety. Any of the RECIST metrics may be used to characterizethe effects of the compounds of the invention on tumors including butnot limited to response, assessment and measurement criteria.

The following examples are intended to illustrate certain embodiments ofthe present teachings, but do not necessarily exemplify the full scopeof the present teachings and therefore should not be construed to limitthe scope of the present teachings.

EXAMPLES Example 1

General procedure for synthesizing a compound of the present teachings:Dihydroxy cisplatin,oxalato[(1R,2R)-1,2-cyclohexanediamine-κN,κN′]dihydroxyplatinum ordichloro[(1R,2R)-1,2-cyclohexanediamine-κN,κN′]dihydroxyplatinum wassuspended in N,N-dimethylformamide and 1-3 equivalents of theappropriate anhydride or isocyanate was added. The solution was stirredat 25-40° C. for 1-5 days. The solution was centrifuged and thendecanted. Unreacted starting material was recovered from decanted solid.The solvent from the filtrate was removed under vacuum and the cruderesidue was purified on silica gel chromatography to afford pureproducts.

The following analogs were prepared according to the above generalprocedure by using the appropriate isocyanate or anhydride:

1: LCMS (Mobile Phase: A: water (0.01% formic acid) B: ACN (0.01% formicacid); Gradient: 5%-40% B in 5.0 minutes (min); Flow Rate: 1.5 ml/min,6.0 min run; Column: CORTECS C18+, 4.6*50 mm, 2.7 um; Oven Temperature:30° C.) Rt: 0.67; MH⁺: 446, 447, 448, 449, 450.

2: LCMS (Mobile Phase: A: water (0.01% TFA) B: ACN (0.01% TFA);Gradient: 5%-95% B in 1.5 min; Flow Rate: 1.8 ml/min, 3.0 min run;Column: SunFire C18, 4.6*50 mm, 3.5 um; Oven Temperature: 45° C.) Rt:1.436; MH⁺: 662.8, 663.8, 664.8.

3: LCMS (Mobile Phase: A: water (0.01% TFA) B: ACN (0.01% TFA);Gradient: 5%-95% B in 1.5 min; Flow Rate: 1.8 ml/min, 3.0 min run;Column: SunFire C18, 4.6*50 mm, 3.5 um; Oven Temperature: 45° C.) Rt:1.684; MH⁺: 555.7, 556.7, 557.7.

4: LCMS (Mobile Phase: A: water (0.01% TFA) B: ACN (0.01% TFA);Gradient: 5%-95% B in 1.5 min; Flow Rate: 1.8 ml/min, 3.2 min run;Column: SunFire C18, 4.6*50 mm, 3.5 um; Oven Temperature: 45° C.) Rt:1.270; MH⁺: 575.1, 576.1, 577.1.

5: LCMS (Mobile Phase: A: water (0.01% TFA) B: ACN (0.01% TFA);Gradient: 5%-95% B in 1.4 min; Flow Rate: 2.3 ml/min, 3.2 min run;Column: SunFire C18, 4.6*50 mm, 3.5 um; Oven Temperature: 50° C.) Rt:2.062; MH⁺: 741.4, 742.4, 743.3.

6: LCMS (Mobile Phase: A: water (0.01% TFA) B: ACN (0.01% TFA);Gradient: 5%-95% B in 1.5 min; Flow Rate: 1.8 ml/min, 3.0 min run;Column: SunFire C18, 4.6*50 mm, 3.5 um; Oven Temperature: 45° C.) Rt:1.450; MH⁺: 572.8, 573.8, 574.87: LCMS (Mobile Phase: A: water (0.01%TFA) B: ACN (0.01% TFA); Gradient: 5%-95% B in 1.5 min; Flow Rate: 1.8ml/min, 3.0 min run; Column: SunFire C18, 4.6*50 mm, 3.5 um; OvenTemperature: 45° C.) Rt: 1.639; MH⁺: 732.8, 733.8, 734.8, 735.8, 736.8

8: LCMS (Mobile Phase: A: water (0.01% TFA) B: ACN (0.01% TFA);Gradient: 5%-95% B in 1.5 min; Flow Rate: 1.8 ml/min, 3.0 min run;Column: SunFire C18, 4.6*50 mm, 3.5 um; Oven Temperature: 45° C.) Rt:1.590; MH⁺: 644.8, 645.8, 646.8, 647.8, 648.8.

9: LCMS (Mobile Phase: A: water (0.01% TFA) B: ACN (0.01% TFA);Gradient: 5%-95% B in 1.5 min; Flow Rate: 1.8 ml/min, 3.0 min run;Column: SunFire C18, 4.6*50 mm, 3.5 um; Oven Temperature: 45° C.) Rt:1.661; MH⁺: 750.8, 751.8, 752.8.

Example 2

To test the effect of a compound described herein on cancer cells, humancancer cell lines were plated in 96 well plates (Costar) and 24 hourslater were treated with a compound for 48-72 hours. Specifically, H460cells (ATCC) were plated at a concentration of 1,500 cells per well andincubated for 48 hours. Compound starting dose was 20 μM and three foldserial dilutions were done for a total of ten samples. Inhibition ofproliferation was measured using Cell Titer-Glo® reagent using thestandard protocol (Promega) and a GloMax® multi+detection system(Promega). Percent proliferation inhibition was calculated using thefollowing formula: % inhibition=(control−treatment)/control*100. Controlis defined as vehicle alone. IC50 curves were generated using nonlinearregression analysis (four parameter) with GraphPad Prism 6.

Compounds of the present teachings each has an IC50 between 0.0001 μMand 50 μM. For example, as shown below, some examples of the presentteachings each has an IC50 value between 0.01 μM and 30 μM. In someembodiments, the compounds have the following IC50.

Compound No. IC₅₀/μM (H460) 3 0.94 6 21.7 8 1.08 2 13.6

These data demonstrate that compounds described herein are efficaciousfor inducing cell death in a cancer cell.

Example 3

To assess the activity of the compounds in vivo, the effect of compound5 on the growth of human Calu-6 NSCLC xenografts was tested. All micewere treated in accordance with the OLAW Public Health Service Policy onHuman Care and Use of Laboratory Animals and the ILAR Guide for the Careand Use of Laboratory Animals, and were conducted at Charles RiverLaboratories (Morrisville, N.C.). All in vivo studies were conductedfollowing the protocols approved by the Charles River InstitutionalAnimal Care and Use Committee. For the Calu-6 in vivo studies, 10 weekold female NCR nude mice were inoculated subcutaneously into the rightflank with 10 million cells in 1:1 RPMI 1640 (Invitrogen, Carlsbad,Calif.)/Matrigel (BD Biosciences, San Jose Calif.). Tumor measurementswere taken twice weekly, using vernier calipers. Tumor volume wascalculated using the formula: V=0.5×width×width×length.

When tumors approached a volume of 100 mm³, mice were randomized intotwo groups of ten animals. Mice were treated with vehicle control (10%Solutol® HS15 in saline) or 30 mg/kg 5 [by intravenous injection. Micewere dosed twice weekly for the duration of the study. Twenty-four hoursafter the final dose tumor volumes were measured again for calculationof tumor growth inhibition. All statistical analysis was done usingGraphPad PRISM® Version 6.00. Final tumor volumes were analyzed usingwith a one-way analysis of variance and Tukey multiple comparison test.Efficacy data for 5 is shown in FIG. 1. Similar experiments were alsoconducted to access the activity of the compounds in other xenograftmodels.

Example 4 Mouse PK/PD Studies

To examine the ability of compounds to accumulate in tumors, a murinecancer model was used. Animals were inoculated with 5×10⁵ H460 smallcell lung cancer cells via subcutaneous injection to the flank. Tumorswere allowed to reach an approximate volume of −500 mm³. Animals werethen randomized into treatment groups of 3 animals per time point andwere dosed at the maximum tolerated dose (MTD). The 24 hour time pointwas used as a benchmark across compounds

Compound No. Dose (mg/kg) 10 8 2 40 5 30 6 50

Tumor platinum levels were determined by inductively coupled plasma massspectrometry (ICP-MS). Tumors were excised from animals and dissolved infuming nitric acid (60% w/w) by adding four parts nitric acid to 1 parttumor w/w and heating overnight at 60 degrees Centigrade. The resultingdigest was diluted 1:10 in ICP-MS analysis buffer (1% nitric acid, 2%Triton® x-100), and directly introduced into the ICP-MS unit byperistaltic pump. The end dilution factor for the samples as introducedto the ICP-MS was 50×.

FIG. 2 shows the platinum levels in the tumor for three exemplarycompounds (Compound 2; Compound 5; and Compound 6 in FIG. 2) of thepresent teachings, respectively, in which each of the compounds wasdosed as a free drug. Compound 10 is

The figure shows higher platinum levels in the tumors for the exemplarycompounds 2, 5 and 6. On the contrary, compound 10, a less polarcompound, has a lower platinum level than compound 2, 5 and 6.

Example 5

The log P of the compounds was measured using a chromatographic methodand by comparison of the retention time with a calibration curvegenerated from known compounds. The following reverse phase HPLC methodwas used: mobile phase: A 95% water/5% ACN/0.1% TFA (Trifluoroaceticacid); B: 95% CAN/water/5% water/0.1% TFA; Gradient 10%-100% B in 8minutes (min),\; Flow rate 1.5 ml/min, 12 min run; Column: ZorbaxEclipse XDB C8, 4.6×100 mm, 3.5 mm; Column temperature: 30° C.

Measured Compound No. Rt (mins) LogP 1 No retention <1 2 1.59 1.00 32.588 1.29 4 No retention <1 5 No retention <1 6 1.854 1.07 7 2.827 1.388 2.551 1.27 9 3.553 1.66 oxaliplatin 0.879 0.83 10  7.618 4.79Reference Literature compounds logP Aniline 0.922 0.9 Benzyl alcohol2.602 1.1 Benzoic acid 3.305 1.9 Nitrobenzene 4.545 1.9 Toluene 5.8382.7 Naphthalene 6.32 3.6 Triphenylamine 8.219 5.7

EQUIVALENTS AND SCOPE

While several embodiments of the present teachings have been describedand illustrated herein, those of ordinary skill in the art will readilyenvision a variety of other means and/or structures for performing thefunctions and/or obtaining the results and/or one or more of theadvantages described herein, and each of such variations and/ormodifications is deemed to be within the scope of the present teachings.More generally, those skilled in the art will readily appreciate thatall parameters, dimensions, materials, and configurations describedherein are meant to be exemplary and that the actual parameters,dimensions, materials, and/or configurations will depend upon thespecific application or applications for which the teachings of thepresent teachings is/are used. Those skilled in the art will recognize,or be able to ascertain using no more than routine experimentation, manyequivalents to the specific embodiments of the present teachingsdescribed herein. It is, therefore, to be understood that the foregoingembodiments are presented by way of example only and that, within thescope of the appended claims and equivalents thereto, the presentteachings may be practiced otherwise than as specifically described andclaimed. The present teachings are directed to each individual featureand/or method described herein. In addition, any combination of two ormore such features and/or methods, if such features and/or methods arenot mutually inconsistent, is included within the scope of the presentteachings.

The scope of the present invention is not intended to be limited to theabove Description, but rather is as set forth in the appended claims.

In the claims, articles such as “a,” “an,” and “the” may mean one ormore than one unless indicated to the contrary or otherwise evident fromthe context. Claims or descriptions that include “or” between one ormore members of a group are considered satisfied if one, more than one,or all of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

It is also noted that the term “comprising” is intended to be open andpermits but does not require the inclusion of additional elements orsteps. When the term “comprising” is used herein, the term “consistingof” is thus also encompassed and disclosed.

Where ranges are given, endpoints are included. Furthermore, it is to beunderstood that unless otherwise indicated or otherwise evident from thecontext and understanding of one of ordinary skill in the art, valuesthat are expressed as ranges can assume any specific value or subrangewithin the stated ranges in different embodiments of the invention, tothe tenth of the unit of the lower limit of the range, unless thecontext clearly dictates otherwise.

In addition, it is to be understood that any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Since such embodiments aredeemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the compositions of the invention can beexcluded from any one or more claims, for any reason, whether or notrelated to the existence of prior art.

All cited sources, for example, references, publications, databases,database entries, and art cited herein, are incorporated into thisapplication by reference, even if not expressly stated in the citation.In case of conflicting statements of a cited source and the instantapplication, the statement in the instant application shall control.

Section and table headings are not intended to be limiting.

What is claimed is:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: two of R¹, R²,R³, and R⁴ each independently is a halide or a carboxylate; theremaining two of R¹, R², R³, and R⁴ each independently is an amine; andX is absent, C(R⁵)₂, or NR⁵, R⁵ and R⁶ independently at each occurrenceis selected from hydrogen, alkyl, alkenyl, alkynyl, ether, amine, andcarboxylate, wherein each of the alkyl, the alkenyl, the alkynyl, theether, and the amine groups optionally is substituted with one or moregroups, each independently selected from halogen, hydroxyl, ether,alkoxy, and amine, wherein each of the ether, the alkoxy, or the amineis optionally substituted with one or more suitable substituents; and atleast one of R¹, R², R³, R⁴, R⁵, and R⁶ comprises a polar moiety.
 2. Thecompound of claim 1, wherein the compound has Formula Ia:


3. The compound of claim 1, wherein at least one of R¹ and R² is anamine.
 4. The compound of claim 1, wherein R¹ and R² are joined togetherto form cyclohexane-1,2-diamine.
 5. The compound of claim 1, wherein R³and R⁴ each is Cl.
 6. The compound of claim 5, wherein the compound hasFormula IIIa:

wherein at least one of R⁵ and R⁶ comprises a polar moiety.
 7. Thecompound of claim 1, wherein R³ and R⁴ are joined together to formoxalic acid.
 8. The compound of claim 7, wherein the compound hasFormula IIIb:

wherein at least one of R⁵ and R⁶ comprises a polar moiety.
 9. Thecompound of claim 1, wherein one of R⁵ and R⁶ is methyl.
 10. Thecompound of claim 1, wherein X or Y is absent.
 11. The compound of claim1, wherein X or Y is CH₂ or C(CH₃)₂.
 12. The compound of claim 1,wherein X or Y is NH.
 14. The compound of claim 1, wherein the compoundis polar.
 15. The compound of claim 1, wherein the compound has a log Pof less than about 2.0.
 16. The compound of claim 1, wherein thecompound has a log P of less than about 1.7.
 17. The compound of claim1, wherein the compound has a log P of less than about 1.3.
 18. Thecompound of claim 1, wherein the compound has a log P of less than about1.1.
 19. A compound selected from:


20. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 21. A method of treating cancerselected from lung cancer, breast cancer, colorectal cancer, ovariancancer, bladder cancer, prostate cancer, cervical cancer, renal cancer,leukemia, central nervous system cancers, myeloma, and melanoma,comprising administering a therapeutically effective amount of acompound of claim
 1. 22. A method of treating cancer selected from lungcancer, breast cancer, colorectal cancer, ovarian cancer, bladdercancer, prostate cancer, cervical cancer, renal cancer, leukemia,central nervous system cancers, myeloma, and melanoma, comprisingadministering a therapeutically effective amount of a composition ofclaim
 20. 23. A method of inhibiting proliferation of a cell comprisingcontacting the cell with an effective amount of a compound of claim 1.24. The method of claim 23, wherein the cell is a cancer cell.